Estimating acute response to cardiac resynchronization therapy

ABSTRACT

Systolic timing intervals are measured in response to delivering pacing energy to a pacing site of a patient&#39;s heart. An estimate of a patient&#39;s acute response to cardiac resynchronization therapy (CRT) for the pacing site is determined using the measured systolic timing intervals. The estimate is compared to a threshold. The threshold preferably distinguishes between acute responsiveness and non-responsiveness to CRT for a patient population. An indication of acute responsiveness to CRT for the pacing site may be produced in response to the comparison.

FIELD OF THE INVENTION

The present invention relates generally to cardiac pacing therapy, andmore specifically, to estimating a patient's acute response to cardiacresynchronization therapy for a pacing site.

BACKGROUND OF THE INVENTION

When functioning normally, the heart produces rhythmic contractions andis capable of pumping blood throughout the body. The heart hasspecialized conduction pathways in both the atria and the ventriclesthat enable the rapid conduction of excitation impulses (i.e.depolarizations) from the SA node throughout the myocardium. Thesespecialized conduction pathways conduct the depolarizations from the SAnode to the atrial myocardium, to the atrio-ventricular node, and to theventricular myocardium to produce a coordinated contraction of bothatria and both ventricles.

The conduction pathways synchronize the contractions of the musclefibers of each chamber as well as the contraction of each atrium orventricle with the opposite atrium or ventricle. Without thesynchronization afforded by the normally functioning specializedconduction pathways, the heart's pumping efficiency is greatlydiminished. Patients who exhibit pathology of these conduction pathwayscan suffer compromised cardiac output.

Cardiac rhythm management devices have been developed that providepacing stimulation to one or more heart chambers in an attempt toimprove the rhythm and coordination of atrial and/or ventricularcontractions. Cardiac rhythm management devices typically includecircuitry to sense signals from the heart and a pulse generator forproviding electrical stimulation to the heart. Leads extending into thepatient's heart chamber and/or into veins of the heart are coupled toelectrodes that sense the heart's electrical signals and for deliveringstimulation to the heart in accordance with various therapies fortreating cardiac arrhythmias.

Pacemakers are cardiac rhythm management devices that deliver a seriesof low energy pace pulses timed to assist the heart in producing acontractile rhythm that maintains cardiac pumping efficiency. Pacepulses may be intermittent or continuous, depending on the needs of thepatient. There exist a number of categories of pacemaker devices, withvarious modes for sensing and pacing one or more heart chambers.

Pacing therapy has been used in the treatment of heart failure (HF). HFcauses diminished pumping power of the heart, resulting in the inabilityto deliver enough blood to meet the demands of peripheral tissues. HFmay cause weakness, loss of breath, and build up of fluids in the lungsand other body tissues. HF may affect the left heart, right heart orboth sides of the heart. For example, HF may occur when deterioration ofthe muscles of the heart produce an enlargement of the heart and/orreduced contractility. The reduced contractility decreases the cardiacoutput of blood and may result in an increased heart rate. In somecases, HF is caused by unsynchronized contractions of the left and rightheart chambers, denoted atrial or ventricular dysynchrony. Particularlywhen the left or right ventricles are affected, the unsynchronizedcontractions can significantly decrease the pumping efficiency of theheart.

Pacing therapy to promote synchronization of heart chamber contractionsto improve cardiac function is generally referred to as cardiacresynchronization therapy (CRT). Some cardiac pacemakers are capable ofdelivering CRT by pacing multiple heart chambers. Pacing pulses aredelivered to the heart chambers in a sequence that causes the heartchambers to contract in synchrony, increasing the pumping power of theheart and delivering more blood to the peripheral tissues of the body.In the case of dysynchrony of right and left ventricular contractions, abiventricular pacing therapy may pace one or both ventricles. Bi-atrialpacing or pacing of all four heart chambers may alternatively be used.

SUMMARY OF THE INVENTION

The present invention is directed to systems and method for estimating apatient's acute response of a patient to cardiac resynchronizationtherapy. Methods of the present invention involve measuring systolictiming intervals based on cardiac events for a patient's heart, andclassifying a response to pacing as an acute responder or non-responder.A pattern recognition or fusion algorithm may be used to classify theresponse to pacing.

A confidence indication of the classification may be produced.Classification of an individual patient's response to CRT pacing ispreferably based on a patient population for acute CRT responsiveness. Apositive indication of an acute response indicates that the pacing sitemeets cardiac electrical performance criteria and provides for improvedpatient hemodynamics.

Methods of the present invention involve measuring systolic timingintervals based on cardiac events for a patient's heart. An estimate ofa patient's acute response to CRT for a pacing site is determined usingthe measured systolic timing intervals. The estimate is compared to athreshold. The threshold preferably distinguishes between acuteresponsiveness and non-responsiveness to CRT for a patient population.An indication of a patient's acute response to CRT for the pacing sitemay be produced in response to the comparison. The systolic timingintervals may be measured for paced beats associated with the pacingsite. The systolic timing intervals may be measured for unpaced beatsassociated with the pacing site.

Producing the indication of a patient's acute response to CRT mayinvolve producing a binary indication of acute responsiveness to CRT forthe pacing site. Producing the indication of a patient's acute responseto CRT may involve producing a confidence indication indicative ofrelative acute responsiveness to CRT for the pacing site. A humanperceivable indication of one or both of the binary indication of anacute response to CRT and the confidence indication may be generated.According to one approach, an electrode of an implantable cardiac leadmay be implanted at the pacing site in response to a positive indicationof an acute response to CRT for the pacing site. One or more pacingparameters, such as an atrio-ventricular delay, may be set forimplementing CRT based on a positive indication of an acute response toCRT and the confidence indication.

According to various embodiments, systolic timing intervals are measuredin response to pacing the pacing site using one or moreatrio-ventricular delay (AVD) values. For example, a short burst pacingprotocol may be implemented for a multiplicity of AVD values. Thesystolic timing intervals may be associated with one or both ofmechanical and electrical activity of the patient's heart. For example,the systolic timing intervals may involve measuring timing intervalsassociated with one or both of heart sounds and arterial blood pressure.Measuring the systolic timing intervals may involve measuring timingintervals associated with cardiac stroke impedance.

In accordance with further embodiments, a medical system of the presentinvention may include one or more electrodes for delivering pacingpulses to a patient's heart, and an energy delivery and sensing unitcoupled to the electrodes. The system may further include a hemodynamicsensor and a memory configured to store at least a threshold thatdistinguishes between acute responsiveness and non-responsiveness to CRTfor a patient population. A controller is coupled to the memory,hemodynamic sensor, and the energy delivery and sensing unit. Thecontroller is configured to measure systolic timing intervals derivedfrom signals produced by the hemodynamic sensor in response to cardiacevents, such as pacing pulses delivered to a pacing site of a patient'sheart, and to compute an estimate of acute responsiveness to CRT for thepacing site using the measured systolic timing intervals and thethreshold.

The controller may be configured to implement a fusion algorithm forcomputing the estimate of acute responsiveness to CRT for the pacingsite. The controller may be configured to compare the estimate to thethreshold and produce an indication of acute responsiveness to CRT forthe pacing site in response to the comparison.

The hemodynamic sensor may include a sensor configured to sensemechanical activity of the patient's heart. For example, the hemodynamicsensor may include a heart sounds sensor. The hemodynamic sensor mayinclude a sensor configured to sense an electrical parameter associatedwith the patient's heart. For example, the hemodynamic sensor mayinclude an impedance sensor, such as a cardiac stroke impedance sensor.

The hemodynamic sensor may include a sensor configured to sensemechanical activity of the patient's heart and a sensor configured tosense electrical activity of the patient's heart (e.g.,electrocardiograms (ECG) or electrograms (ECG)), and the controller maybe configured to measure systolic timing intervals derived from featuresof signals produced by the mechanical and electrical activity sensors.For example, the hemodynamic sensor may include a cardiac strokeimpedance sensor and a heart sounds sensor, and the controller may beconfigured to measure the systolic timing intervals derived fromfeatures of signals produced by the cardiac stroke impedance sensor andthe heart sounds sensor. By way of further example, the hemodynamicsensor may include a heart sounds sensor and an electrical sensor thatmay sense intracardiac electrograms, and the controller may beconfigured to measure the systolic timing intervals derived fromfeatures of signals produced by the heart sounds sensor and the EGMsensor. One such feature could be the pre-ejection period (Q-S1 orR-S1), for example.

The medical system may be configured for implantation in a patient. Insome embodiments, at least a portion of the system may be configured forimplantation in a patient and another portion of the system may beconfigured for operation external to the patient. For example, at leasta sensor configured for sensing an electrical parameter or electricalactivity of the patient's heart may be implantable or configured forinvasive use. Other portions of the system, such as a processor, energydelivery circuitry, sensing circuitry, and signal processing software,may be provided in devices and/or systems that reside external of thepatient. Such patient-external devices and/or systems may be situatednear the patient, such as in the case of a programmer or bed-sidecommunicator, or situated remotely of the patient, such as in the caseof a networked advanced patient management system (e.g., distributedsystems). Some system elements, such as a processor, memory, or certainsoftware, for example, may be configured for both patient-internal andpatient-external use or operation. It is understood that one or moreelements of a medical system of the present invention may be configuredfor implantation in a patient, and one or more elements of the medicalsystem may be configured for patient-external operation, and that theexamples of various system configurations described herein are fornon-limiting illustrative purposes only.

The above summary of the present invention is not intended to describeeach embodiment or every implementation of the present invention.Advantages and attainments, together with a more complete understandingof the invention, will become apparent and appreciated by referring tothe following detailed description and claims taken in conjunction withthe accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows various waveforms depictive of a cardiac cycle, from whichtiming intervals may be measured and used for evaluating acuteresponsiveness of a pacing site in accordance with embodiments of thepresent invention;

FIG. 2 is a plot of data acquired for a population of CRT patientsuseful for evaluating a pacing site in accordance with the presentinvention;

FIGS. 3 and 5 are plots that illustrate a threshold that is selected todistinguish between acute responders and non-responders for a populationof CRT patients in accordance with embodiments of the present invention;

FIGS. 4 and 6 are plots of specificity (1-specificity) versussensitivity for acute responsiveness detection, which may be determinedusing the threshold shown in FIGS. 4 and 6, respectively;

FIGS. 7 and 8 are flow charts that illustrate various processesassociated with a pacing site evaluation methodology in accordance withembodiments of the present invention;

FIG. 9 is a block diagram of circuitry that may be used for implementinga pacing site evaluation methodology in accordance with embodiments ofthe present invention; and

FIG. 10 illustrates a patient-implantable device that may be used inconjunction with a pacing site evaluation methodology in accordance withembodiments of the present invention.

While the invention is amenable to various modifications and alternativeforms, specifics thereof have been shown by way of example in thedrawings and will be described in detail below. It is to be understood,however, that the intention is not to limit the invention to theparticular embodiments described. On the contrary, the invention isintended to cover all modifications, equivalents, and alternativesfalling within the scope of the invention as defined by the appendedclaims.

DETAILED DESCRIPTION OF VARIOUS EMBODIMENTS

In the following description of the illustrated embodiments, referencesare made to the accompanying drawings, which form a part hereof, and inwhich is shown by way of illustration, various embodiments in which theinvention may be practiced. It is to be understood that otherembodiments may be utilized, and structural and functional changes maybe made without departing from the scope of the present invention.

Systems, devices or methods according to the present invention mayinclude one or more of the features, structures, methods, orcombinations thereof described hereinbelow. For example, a device orsystem may be implemented to include one or more of the advantageousfeatures and/or processes described below. It is intended that suchdevice or system need not include all of the features described herein,but may be implemented to include selected features that provide foruseful structures and/or functionality. Such a device or system may beimplemented to provide a variety of therapeutic or diagnostic functions.

Embodiments of the invention are directed to systems and methods forestimating a patient's acute response to cardiac resynchronizationtherapy (CRT). Embodiments of the invention are directed to selecting apacing site for CRT during implant or after implant that provides forimproved hemodynamics.

Aspects of the invention involve measuring systolic timing intervals andusing a classification methodology to classify a cardiac response topacing as an acute responder or non-responder to CRT. An acute respondergenerally refers to a stimulation site and device parameter (e.g.,atrio-ventricular delay) that will likely provide a positive hemodynamicresponse to CRT. A non-responder generally refers to a stimulation sitethat is unlikely to provide a positive hemodynamic response to CRT.According to embodiments of the invention, a pattern recognition orfusion analysis may be performed to facilitate classification of acardiac response to pacing as indicative of acute responsiveness ornon-responsiveness to CRT. Classification may further involve providinga confidence indication of acute responsiveness or non-responsiveness.

Systems and methods of the invention may involve, for example, measuringsystolic timing intervals in response to delivering pacing energy to apacing site of a patient's heart using one or more pacing parametervalues. An estimate of acute responsiveness to cardiac resynchronizationtherapy (CRT) for the pacing site may be estimated using the measuredsystolic timing intervals. The estimate may be compared to a threshold.The threshold is preferably developed from data acquired for apopulation of CRT patients and distinguishes between acuteresponsiveness and non-responsiveness to CRT. An indication of acuteresponsiveness to CRT for the pacing site is produced in response to thecomparison, such as a signal or a human perceivable indication.

In various embodiments, a binary indication of acute responsiveness toCRT for the pacing site is produced. The binary indication, such aspass/fail or yes/no, provides an immediately understandable indicationto an electronic or human recipient that the pacing site is or is not anacute responder site. In addition to the binary indication, a confidenceindication indicative of relative acute responsiveness to CRT for thepacing site may also be produced. The confidence indication may beprovided in various forms, such as a percentage or probability ofcertainty, or a gradation or level of confidence, such as high, mediumor low.

Methods and systems of the invention provide for identification ofcandidate pacing sites, such as during an implant procedure, andverification of existing pacing sites, such as during ambulatoryevaluation, that a given site is an acute responder site for bothelectrical and hemodynamic perspectives. A pacing site evaluationmethodology of the present invention advantageously provides anindication that a pacing site identified as an acute responder site willlikely provide for improved patient hemodynamics relative to pacingsites that merely meet electrical performance requirements for pacing atthe site.

Moreover, a determination that a given pacing site will likely providefor improved patient hemodynamics may be made without testing at amultiplicity of sites, comparing results for each of the sites, andselecting the “best” site among those tested based on the comparison. Insuch conventional approaches, selection of the “best site” is based onelectrical performance, typically without quantitatively assessinghemodynamic performance associated with pacing at the “best” site. Incontrast to conventional evaluation approaches, a pacing site evaluationmethodology of the present invention provides an indication of whetheror not a given pacing site is an acute responder that will likelyprovide for improved patient hemodynamics based on the evaluationperformed for the given pacing site, and does not require comparison oftesting results for a multiplicity of sites.

Further, it has been found from clinical testing that optimization ofpacing parameters, such as atrio-ventricular delay (AVD), is largelysolved by determining acute responsiveness of a given pacing site in amanner consistent with methodologies of the present invention. Forexample, once a pacing site has been identified as an acute responderusing methodologies of the present invention, one or more pacingparameters (AVD and/or inter-ventricular delay (IVD) may be set based onthe level of acute responsiveness of the pacing site. For a strongresponder site, for example, setting the AVD to about 120 ms is believedadequate. For a weak responder site, longer AVD settings are believedappropriate. For example, weak responder sites or non-responder sitesmay have associated AVD settings of about 80% of the PR interval, whilestrong responder sites may have associated AVD settings of about 120 ms.

Turning now to FIG. 1, there is shown various waveforms depictive of acardiac cycle. FIG. 1 shows waveforms developed from ECG, cardiac strokeimpedance, and heart sound sensing. A number of features are also shownfor each of the waveforms. Timing intervals useful for evaluating acuteresponsiveness of a pacing site in accordance with the present inventionmay be developed based on features of one or a combination of thewaveforms shown in FIG. 1. It is understood that timing intervals usefulfor implementing embodiments of the present invention may be developedusing a wide variety of sensors, waveforms, waveform features, andcombinations of sensors, waveforms and waveform features, and that thoseassociated with FIG. 1 and other figures are provided for non-limitingillustrative purposes only, and should not be construed as limiting thescope of the present invention.

The waveforms shown in FIG. 1 are generally depictive of a singlecardiac cycle, as best seen in the ECG waveform 10. The waveforms 20,30, 40 are aligned with respect to the initiation of ventriculardepolarization as indicated by the Q feature of ECG waveform 10.Waveform 20 represents changes in cardiac stroke impedance during thecardiac cycle. Waveform 30 represents the first derivative of thecardiac stroke impedance waveform 20. Waveform 40 represents heartsounds (S1-S4) associated with different portions of the cardiac cycle.

With reference to waveform 30, and as reflected in waveform 20, variouswaveform features of interest are identified by letters A, B, C, X, Y,and O. Feature A is associated with contraction of the atria. Feature Bis associated with opening of the aortic valve. Feature C is associatedwith maximum systolic blood flow. Feature X is associated with closureof the aortic valve. Feature Y is associated with closure of thepulmonary valve, and feature O is associated with opening of the mitralvalve.

Decreasing rates of cardiac stroke impedance change are recorded asupward deflections in the tracing of waveform 30. The A wave correspondsto atrial systole. The C wave corresponds to the ventricular systole andreflects the rate of change of speed of ejection of the pattern ofejection of blood from the ventricles. The O wave corresponds toventricular diastole and reflects the rate of change of volume of theatria and veins. Most of the O wave peak corresponds to the mitralopening. The B point and the X point appear immediately after the aorticvalve opens and closes, respectively. The B point also coincides withthe middle portion of the first heart sound, S1 of waveform 40, and theX point coincides with the second heart sound, S2. The peak C coincideswith the peak flow time measured on the ascending aorta. The S3 heartsound occurs after the O wave maximum (during the descending portion)and corresponds to the rapid filling wave of the ventricle. The fourthheart sound, S4, occurs during the second phase of ventricular filling,when the atria contract just prior to S1.

Timing intervals useful in the context of the present invention may bedetermined using features from any or a combination of the waveformsshown in FIG. 1. For example, a timing interval of interest may bedetermined from the timing difference between a feature in the impedancesignal 20, 30 and a feature in the heart sounds signal 40. The followingare non-limiting examples of timing differences of features that may beused in the context of the present invention: S4-B, S4-C, B-S2, C-S2,S1-B, S1-X, S1-Y, S1-O, S2-Y, S2-X, S2-O, X-S3, Y-S3, O-S3. It is notedthat each of these timing differences can be calculated from heart soundonly or impedance only. For example, left ventricular ejection time(LVET) can be calculated as the S1-S2 duration or the B-X duration.

It is understood that LVET is correlated to stroke volume, cardiacoutput, and, in general, the systolic performance of the left ventricle.The pre-ejection period (PEP), for example, can be measured as Q-S1 orQ-B and is inversely correlated to systolic performance and strokevolume, and directly correlated with increasing left atrial pressures.The S2-S3 time difference, also measured as B-S3 or S2-O time, isinversely correlated with the left atrial pressures.

Hence, by using a combination of the above timings, reduced strokevolume or increased filling pressures may be detected. For exampleLVET/PEP is known to be correlated with stroke volume. Also, the time(Q−S1)/(S2−S3) is correlated with left atrial pressures. Using acombination of the above mentioned timing intervals, decompensation canbe detected, such as by trending timing intervals and detecting when athreshold has been crossed.

FIG. 2 is a plot of data acquired for a population of CRT patientsuseful for evaluating a pacing site in accordance with the presentinvention. The patient population preferably includes patients withimplanted cardiac rhythm management devices that provide CRT. Typicalpatients of interest are those who have implanted CRT devices because ofindications such as having QRS complex widths >150 ms or are consideredHF class 3 patients. The patient population may also include patientswith QRS complex widths of <120 ms, but have other indications thatclassify them as CRT patients. The data reflected in FIG. 2 was acquiredfrom some 29 patients, from which systolic timing intervals weremeasured based on left ventricular pressure sensing. As discussed above,equivalent data to that shown in FIG. 2 may be developed from heartsounds data, alone or in combination with pressure data (and/or ECGdata).

According to embodiments of the invention, a fusion algorithm may betrained based on acute CRT responsiveness data for a population of CRTpatients, such as that shown in FIG. 2. A variety of fusion algorithmsand processing methodologies may be used, including, but not limited to,linear regression, Bayesian classification, clustering, support vectormachines, neural networks, among others. In general terms, the fusionalgorithm and processing methodology is used to combine a multiplicityof systolic timing intervals and to provide an estimate (e.g.,probability) that the patient will respond to CRT at the current pacingsite. The fusion algorithm may also be implemented to operate on ablending of data types, such as systolic timing intervals and signalamplitudes, feature attributes (e.g., QRS width) or other aspects ofsensed physiological or hemodynamic conditions and/or patientdemographics. For example, heart sound timing intervals and heart soundamplitudes may be operated on by the fusion algorithm.

In FIG. 2, the ratio of LVET/PEP is shown plotted along the x-axis as afunction of peak left ventricular pressure change (y-axis), denoted asdp/dt given in mmHg/sec. The data shown in FIG. 2 was acquired for pacedbeats, which resulted in stimulation-induced systolic cycles from whichsystolic timing intervals of interest were measured. The systolic timinginterval data acquired for this population of CRT patients was subjectto linear regression, which measures the degree of fit between the lineand the data points. The square deviations are added to create ameasure, R², referred to as the coefficient of determination or R²statistic. This statistic measures the goodness of the fit or the amountof variance explained by the regression model, as is well understood inthe art. Other statistics associated from the regression model may be ofinterest, such as the F statistic, which is a measure of confidence ofthe result.

A logistic regression algorithm, for example, may be developed for amultiplicity of systolic timing intervals and trained based on acute CRTresponsiveness data for a population of CRT patients, an example ofwhich is provided below:u=A+B ₁ X ₁ +B ₂ X ₂ + . . . +B _(K) X _(K)  [1]

In Equation [1], the variable X₁=1/PEP, X₂=LVET, and X₃=1/LVEMD, and Ais a constant. Each of these variables is shown in FIG. 2, and may bemeasured from waveform features associated with one or a combination ofmechanical (e.g., heart sounds, pressure) features, electrical cardiacactivity features, and patient demographic data (e.g., QRS width).

Using the result of Equation [1] above, an estimate of acuteresponsiveness to CRT therapy for the patient may be determined, such asby using the following equation:

$\begin{matrix}{{\overset{\Cap}{P}}_{i} = \frac{{\mathbb{e}}^{u}}{1 + {\mathbb{e}}^{u}}} & \lbrack 2\rbrack\end{matrix}$where P-hat is the estimated probability that the i_(th) case is in acategory and u is the regular linear regression equation. It isunderstood that fewer or greater than three variables may be used in thefusion algorithm. For example, additional timing intervals or otherphysiological or patient-related parameters may be added to Equation [1]above as respective variables X₄, X₅ . . . X_(K). The coefficients B₁ .. . B_(K) in Equation [1] can be determined from the training of thelinear regression algorithm using patient population data. The accuracyof the estimate produced by Equations [1] and [2] above can be improvedby increasing the amount and quality of patient population data used totrain the fusion algorithm.

The estimate or probability provided by the fusion algorithm ispreferably compared to a threshold that distinguishes between acuteresponsiveness and non-responsiveness to CRT for a patient population,as indicated in the following equation:If P(response)≧Th, then patient is an acute responderIf P(response)<Th, then patient is a non-responder  [3]where P(response) refers to the estimate or probability ofresponsiveness indicated by the fusion algorithm result, and Th is thethreshold that distinguishes between acute responsiveness andnon-responsiveness to CRT for a patient population.

The threshold is preferably associated with a sensitivity andspecificity that can reliably distinguish between acute responsivenessand non-responsiveness to CRT for a patient population. Sensitivityrefers to the ability of a test to detect a condition when present.Specificity refers to the ability of a test to exclude a condition whenit is absent. The higher the specificity, the lower the false positives.For example, the threshold may be associated with a sensitivity of 90%and a specificity of 80%.

Turning now to FIGS. 3-6, these figures illustrate examples ofthresholds developed in accordance with the present invention and therelationship between thresholds and associated sensitivity andspecificity values. FIGS. 3 and 4 correspond to a response defined asthe change in LVdpdt>0% from baseline. That is, if a patient has a dpdtof 1000 at baseline and if pacing changes the dpdt to 999, for example,then the patient is a non-responder. If, however, pacing changes thedpdt to 1001, then the patient is a responder. FIGS. 5 and 6 correspondto a response defined as the change in LVdpdt>5% from baseline. That is,if a patient has a dpdt of 1000 at baseline and if pacing changes thedpdt to 1010, for example, then the patient is a non-responder, sincethe change is only 1% compared to the baseline of 1000. If, however,pacing changes the dpdt to 1051, then the patient is a responder, sincean acute response in this illustrative example is defined as a change ofat least 5% of LVdpdt from baseline.

The baseline may be established in several ways. According to oneapproach, the baseline may be determined from systolic timing intervalsmeasured for sensed beats. In embodiments where additional sensormeasurements and/or demographic data is used, this data is also acquiredfor sensed beats. According to another approach, the baseline may beobtained via right ventricular-only pacing (i.e., without leftventricular pacing). Other approaches for establishing the baseline fromwhich responsiveness to pacing can be determined are also contemplated.

In accordance with one approach for establishing the baseline, a leadmay be placed at appropriate locations in or on the heart. Systolictiming intervals may be measured for a number of unpaced beats (i.e.,sensed beats). Additional systolic timing intervals may be measured forpaced beats, preferably using several different atrio-ventricular delaysettings. The systolic timing intervals measured for both paced andsensed beats may then be used to assess the patient's response.

The plot of FIG. 3 illustrates a threshold 105 that is selected todistinguish between acute responders and non-responders for a populationof CRT patients. The value of 0 along the x-axis indicatesnon-responders and the value of 1 indicates responders to CRT. As isshown in FIG. 3, the threshold 105 is selected so that the acuteresponders are distinguished from non-responders with relatively nooverlap between these two classes. In this regard, the threshold 105 isassociated with a relatively high sensitivity and a relatively highspecificity, as indicated in FIG. 4. In the illustrative example of FIG.3, the threshold is about 0.82.

In FIG. 5, the threshold 107 is selected to that the acute respondersare distinguished from non-responders with some degree of overlapbetween these two classes. In this regard, the threshold 107 isassociated with a relatively high sensitivity and a moderately highspecificity, as indicated in FIG. 6. In the illustrative example of FIG.5, the threshold is about 0.64. It has been found that reliabledeterminations of acute responsiveness to CRT for a patient can beachieved using a threshold that is associated with a relatively highsensitivity and a moderately high specificity, such as that shown inFIG. 5.

Turning now to FIG. 7, there is shown a flow chart that illustratesvarious processes associated with a pacing site evaluation methodologyof the present invention. The evaluation involves delivering pacingpulses to a current pacing site 210. The pacing site may be a site atwhich a pacing electrode is presently implanted or a candidate site forimplantation. A short burst pacing protocol is preferably implemented bythe implanted cardiac rhythm management (CRM) device, so that baroreflexis not activated, and afterload is held steady. The pacing protocol maybe implemented using one or more predetermined pacing parameter values(e.g., AVD and/or IVD) or a range of pacing parameter values. Forexample, the pacing protocol may be implemented by sweeping through amultiplicity of AVD value settings.

The pacing protocol produces stimulation-induced systolic cycles fromwhich various systolic timing intervals may be measured 212. Asdiscussed previously, a wide variety of timing intervals and timinginterval combinations may developed from sensing of electrical and/ormechanical activity of the heart. It is noted that the sensor or sensorsused to sense electrical and/or mechanical activity of the heart may beimplanted, patient-external or a combination thereof. For example, anelectrical and/or mechanical heart activity sensor (e.g., heart soundsensor, such as a microphone or accelerometer) may be positioned on theouter skin surface of the patient during a pacing electrode implantprocedure. In an ambulatory scenario, an implanted electrical and/ormechanical heart activity sensor may be used to sense cardiac activityfrom which timing intervals of interest may be measured. The systolictiming intervals may include those identified hereinabove, such as LVETand PEP in particular.

An estimate of acute responsiveness to CRT is computed 214 for the site,preferably by using the methodology discussed above. The computedestimate may then be compared 216 to a threshold, such as that discussedabove. An indication of acute responsiveness of the site may be produced218 based on the comparison. The indication may involve generation of asignal that can be communicated to a processor or other device, such asa programmer, portable communicator, or network interface of an advancedpatient management system, for example. A human perceivable indicationof acute responsiveness may be produced, such as a message presented ona display or activation of a visual/audible indicator (e.g., audibletone, LED illumination or flashing) that indicates the result of thecomparison operation.

In various embodiments, a binary indication of acute responsiveness toCRT for the pacing site is produced to indicate the result of thecomparison operation. The binary indication may be a pass/fail or yes/noindication of whether or not the pacing site is an acute responder site.A confidence indication representative of relative acute responsivenessto CRT for the pacing site may also be produced. As previouslydiscussed, the confidence indication may be provided in various forms,such as a percentage or probability of certainty, variance, or agradation or level of confidence, such as high, medium or low.

FIG. 8 illustrates various processes associated with a pacing siteevaluation methodology of the present invention. In particular, FIG. 8illustrates a methodology involving collection 230 of data for apopulation of CRT indicated patients. A fusion algorithm may be trained232 using the patient population data. Useful fusion algorithms that maybe employed include any regression or classification algorithm can beused to predict CRT responsiveness at a pacing site. Such fusionalgorithms include linear regression, a linear discriminateanalysis-based classifier, support vector machines for both regressionand classification, and neural networks, among others. Based on fusionalgorithm training, a threshold that distinguishes between acuteresponder sites and non-responder sites may be set.

Using the fusion algorithm, an estimate or probability that a givenpacing site will be an acute responder site for a particular patient maybe determined 234, which generally involves comparing the estimate orprobability to a pre-established threshold of the type discussed above.An indication of acute responsiveness or non-responsiveness of thecurrent pacing site may be produced 236 based on the output from thefusion algorithm.

A pacing site evaluation methodology of the present invention may beimplemented in a variety of medical diagnostic devices and systems,include implantable and patient-external devices and systems. Forexample, a pacing site evaluation methodology of the present inventionmay be implemented entirely by an implanted device (e.g., pacemaker,ICD, CRT devices), entirely by a patient-external system (other thancardiac electrodes/leads) or in a distributed manner by both implantedand patient-external devices or systems. In the context of apatient-external or distributed approach, various external systems maybe employed, such as a programmer and/or a networked system, such as anadvanced patient management system.

FIG. 9 is a block diagram of circuitry that implements a pacing siteevaluation methodology in accordance with embodiments of the invention.One or more cardiac electrodes 345 may be positioned or disposed atmultiple locations within a heart chamber or vasculature. In the contextof an electrode implantation procedure, a candidate pacing site may beevaluated using a lead that includes one or more electrodes. In thecontext of post-implant evaluations, one or more implanted pacing sitesmay be evaluated.

One or more sensors 310 are configured to sense physiological factorsindicative of a patient's hemodynamic status. Useful sensors 310 includea sensor or sensors that detect heart sounds (e.g., microphone,accelerometer), a pressure sensor (e.g., left arterial pressure sensorsuch as a pulmonary artery pressure sensor, right ventricular pressuresensor), and a cardiac stroke impedance sensor, among others. Signalsproduced by the one or more sensors 310 may be communicated to ahemodynamic signal processor 330, which processes the sensor signals foruse by a controller 325.

The controller 325 is coupled to the hemodynamic signal processor 330,memory 320, cardiac signal sensing circuitry 340, and pacing therapycircuitry 335. The memory 320 is configured to store programinstructions and/or data. In addition, the stored information may beused to provide a log of events for display or analysis at a later time.The memory 320 may be configured to store a fusion algorithm 301 and athreshold of a type described previously. Alternatively, the fusionalgorithm 301 may be stored on a patient-external device or system. Thecontroller 325 executes program instructions to implement a pacing siteevaluation procedure in accordance with embodiments of the presentinvention.

The controller 325 is preferably coupled to communications circuitry 315which allows the device to communicate with other devices, such as apatient-external programmer or advanced patient management system. Insome implementations, an advanced patient management (APM) system may beused to collect CRT patient data for purposes of developing patientpopulation data from which a fusion algorithm may be trained. This datamay be acquired from numerous CRT patients. The APM system or programmermay also be used to implement or facilitate implementation of the pacingsite evaluation methodology of the present invention, particularly inthe context of an electrode implantation procedure. Methods, structures,and/or techniques described herein, may incorporate various APM relatedmethodologies, including features described in one or more of thefollowing references: U.S. Pat. Nos. 6,221,011; 6,270,457; 6,277,072;6,280,380; 6,312,378; 6,336,903; 6,358,203; 6,368,284; 6,398,728; and6,440,066, which are hereby incorporated herein by reference.

FIG. 10 shows an embodiment of the present invention implemented withuse of an implanted cardiac therapy device 400. The therapy device 400includes cardiac rhythm management circuitry enclosed within animplantable housing 401. The CRM circuitry is electrically coupled to anintracardiac lead system 410. Portions of the intracardiac lead system410 are shown inserted into the patient's heart. The lead system 410includes cardiac pace/sense electrodes 451-456 positioned in, on, orabout one or more heart chambers for sensing electrical signals from thepatient's heart and/or delivering pacing pulses to the heart. Theintracardiac sense/pace electrodes 451-456 may be used to sense and/orpace one or more chambers of the heart, including the left ventricle,the right ventricle, the left atrium and/or the right atrium. The leadsystem 410 may include one or more defibrillation electrodes 441, 442for delivering defibrillation/cardioversion shocks to the heart.

The left ventricular lead 405 incorporates multiple electrodes 454 a-454d positioned at various locations within, on or about the leftventricle. Stimulating the ventricle at multiple locations or at asingle selected location may provide for increased cardiac output in apatients suffering from HF. In accordance with various embodimentsdescribed herein, one or more of the electrodes 454 a-454 d are selectedfor pacing the left ventricle. In other embodiments, leads havingmultiple pacing electrodes positioned at multiple locations within achamber, such as the one illustrated by the left ventricular lead 405 ofFIG. 10, may be implanted within any or all of the heart chambers. A setof electrodes positioned within one or more chambers may be selected.Electrical stimulation pulses may be delivered to the chambers via theselected electrodes according to a timing sequence and outputconfiguration that enhances cardiac function.

Portions of the housing 401 of the implantable device 400 may optionallyserve as one or multiple can or indifferent electrodes. The housing 401is illustrated as incorporating a header 489 that may be configured tofacilitate removable attachment between one or more leads and thehousing 401. The housing 401 of the therapy device 400 may include oneor more can electrodes 481 b. The header 489 of the therapy device 400may include one or more indifferent electrodes 481 a.

The housing 401 and/or header 489 may include one or more hemodynamicsensors 482, such as an accelerometer or microphone. One or more cardiacleads 410 or separate sensor leads may incorporate one or morehemodynamic sensors, such as a pulmonary arterial pressure sensor. Thecardiac electrodes and/or other sensors disposed within or on thehousing 401 or lead system 410 of the therapy device 400 may producesignals used for detection and/or measurement of various physiologicalparameters, such as transthoracic impedance, respiration rate, minuteventilation, heart rate, cardiac dysynchrony, activity, posture, bloodchemistry, O2 saturation, heart sounds, wall stress, wall strain,hypertrophy, inter-electrode impedance, electrical delays (PR interval,AV interval, QRS width, etc.), activity, cardiac chamber pressure,cardiac output, temperature, heart rate variability, depolarizationamplitudes, depolarization timing, and/or other physiologicalparameters. It is contemplated that, in certain embodiments, informationderived from such signals may be incorporated into the fusion algorithmthat is employed to determine acute responsiveness of a pacing site toCRT.

In some configurations, the implantable device 400 may incorporate oneor more transthoracic impedance sensors that may be used to acquire thepatient's respiratory waveform, and/or to acquire otherrespiratory-related information. The transthoracic impedance sensor mayinclude, for example, one or more intracardiac electrodes 441, 442,451-456 positioned in one or more chambers of the heart. Theintracardiac electrodes 441, 442, 451-456 may be coupled to impedancedrive/sense circuitry positioned within the housing 401 of the therapydevice 400. Information from the transthoracic impedance sensor may beused to adapt the rate of pacing to correspond to the patient's activityor metabolic need, among other uses.

Communications circuitry is disposed within the housing 401 forfacilitating communication between the CRM circuitry and apatient-external device, such as an external programmer or advancedpatient management (APM) system. The communications circuitry may alsofacilitate unidirectional or bidirectional communication with one ormore implanted, external, cutaneous, or subcutaneous physiologic ornon-physiologic sensors, patient-input devices and/or informationsystems.

In certain embodiments, the therapy device 400 may include circuitry fordetecting and treating cardiac tachyarrhythmia via defibrillationtherapy and/or anti-tachyarrhythmia pacing (ATP). Configurationsproviding defibrillation capability may make use of defibrillation coils441, 442 for delivering high energy shocks to the heart to terminate ormitigate tachyarrhythmia.

In some embodiments, the implantable therapy device 400 may includecircuitry for selection of pacing electrode(s), timing sequence, and/oramplitude or pulse waveform output configurations (collectively referredto as pacing output configuration) to be applied via one or multipleelectrodes within one or multiple heart chambers. For example, a pacingsite evaluation procedure may be implemented to evaluate, after implant,whether a particular pacing site continues to qualify as an acuteresponder site. In the event of an adverse change in CRT responsivenessoccurring at a particular pacing site, alternative pacing sites orvectors may be evaluated in accordance with the pacing site evaluationmethodologies of the present invention. A change may be made in thepacing output configuration in response to the evaluation. For example,in a pacemaker equipped with multiple pacing electrodes respectivelydisposed at multiple pacing sites within a heart chamber, the ability toselect one or more electrodes, temporal sequence, and/or pulse waveformcharacteristics for delivery of pacing can be used enhance thecontractile function of the heart chamber.

Multi-site pacemakers, such as illustrated herein, are capable ofdelivering pacing pulses to multiple sites of the atria and/orventricles during a cardiac cycle. Certain patients may benefit fromactivation of parts of a heart chamber, such as a ventricle, atdifferent times in order to distribute the pumping load and/ordepolarization sequence to different areas of the ventricle. Amulti-site pacemaker has the capability of switching the output ofpacing pulses between selected electrodes or groups of electrodes withina heart chamber during different cardiac cycles. For example, the pacingpulses may be delivered to the heart chamber at specified locations andat specified times during the cardiac cycle to enhance the synchrony ofthe contraction. Amplitude, pulse duration, anodal/cathodal polarityand/or waveshape of the pacing pulses may also be altered to enhancepumping function.

Various modifications and additions can be made to the preferredembodiments discussed hereinabove without departing from the scope ofthe present invention. Accordingly, the scope of the present inventionshould not be limited by the particular embodiments described above, butshould be defined only by the claims set forth below and equivalentsthereof.

1. A medical system, comprising: an electrode for delivering at leastone pacing pulse to a pacing site of a patient's heart during a cardiaccycle; an energy delivery and sensing unit coupled to the electrode; ahemodynamic sensor; another sensor; a memory configured to store atleast a threshold that distinguishes between acute responsiveness andnon-responsiveness to cardiac resynchronization therapy (CRT) for apatient population, patient population data, and a fusion algorithm; anda controller coupled to the memory, the hemodynamic sensor, the anothersensor, and the energy delivery and sensing unit, the controllerconfigured to: measure systolic timing intervals of a plurality ofdifferent events of the cardiac cycle derived from a plurality ofsignals sensed during the cardiac cycle, at least one of the pluralityof signals produced by the hemodynamic sensor and indicating a systolictiming interval of a mechanical cardiac event of the plurality ofdifferent events of the cardiac cycle, and at least another of theplurality of signals produced by the another sensor, implement thefusion algorithm to combine the measured systolic timing intervals ofthe plurality of different events of the cardiac cycle and the patientpopulation data to compute an estimate of probability of acuteresponsiveness to cardiac resynchronization therapy CRT for the pacingsite, compare the estimate to the threshold, and generate an outputindication of acute responsiveness or non-responsiveness of the pacingsite to CRT based on the comparison of the estimate to the threshold. 2.The medical system of claim 1, wherein all of the plurality of systolictiming intervals are intervals of different mechanical events of thecardiac cycle.
 3. The medical system of claim 1, wherein the controlleris configured to measure signal amplitude from at least one of thesignals of the plurality and implement the fusion algorithm using themeasured systolic timing intervals and the at least one measured signalamplitude.
 4. The medical system of claim 1, wherein controllerimplementation of the fusion algorithm comprises use of a linearregression parameter generated from the measured systolic timingintervals in computing the estimate.
 5. The medical system of claim 1,wherein at least one of the signals of the plurality from which at leastone of the systolic timing intervals is measured comprises an electricalcardiac signal indicating electrical activity of the heart during thecardiac cycle.
 6. The medical system of claim 1, wherein the hemodynamicsensor comprises a cardiac stroke impedance sensor.
 7. The medicalsystem of claim 1, wherein the hemodynamic sensor comprises a heartsounds sensor.
 8. The medical system of claim 1, wherein the hemodynamicsensor comprises a cardiac stroke impedance sensor and a heart soundssensor, the controller measuring the systolic timing intervals derivedfrom features of signals produced by the cardiac stroke impedance sensorand the heart sounds sensor.
 9. The medical system of claim 1, whereinthe system is configured for implantation in a patient.
 10. The medicalsystem of claim 1, wherein at least a portion of the system isconfigured for implantation in a patient and another portion of thesystem is configured for operation external to the patient.
 11. Themedical system of claim 1, wherein the plurality of systolic timingintervals are intervals of different electromechanical events of thecardiac cycle.
 12. The medical system of claim 1, wherein the computedestimate of acute responsiveness is a binary indication between acuteresponsiveness and non-responsiveness to CRT for the pacing cite. 13.The medical system of claim 1, wherein the controller is furtherconfigured to calculate a confidence indication indicative of relativeacute responsiveness to CRT for the pacing site.
 14. The medical systemof claim 13, wherein the controller is further configured to set anatrio-ventricular delay for the CRT based on the estimate of acuteresponsiveness to CRT and the confidence indication.
 15. The medicalsystem of claim 1, further comprising circuitry configured to output ahuman perceivable indication indicative of the computed estimate ofacute responsiveness to CRT.
 16. The medical system of claim 1, whereinthe systolic timing intervals are measured in response to delivery ofthe at least one pacing pulse using one or more atrio-ventricular delayvalues.
 17. The medical system of claim 1, wherein the hemodynamicsensor comprises an arteriole blood pressure sensor configured forimplantation and to measure pressure of the arteriole system.
 18. Amedical system for delivering at least one pacing pulse to a pacing siteof a patient's heart during a cardiac cycle, the system comprising:means for measuring systolic timing intervals of a plurality ofdifferent events of the cardiac cycle, at least one of the systolictiming intervals based on a mechanical cardiac event, the measuringmeans comprising at least a hemodynamic sensor and another sensor; meansfor storing patient population data; means for implementing a fusionalgorithm to combine the measured systolic timing intervals of theplurality of different events of the cardiac cycle and the patientpopulation data to compute an estimate of acute responsiveness tocardiac resynchronization therapy (CRT); means for comparing theestimate to a threshold, the threshold distinguishing between acuteresponsiveness and non-responsiveness to CRT for a patient population;and means for producing an indication of acute responsiveness to CRT forthe pacing site in response to the comparison.